The present invention relates to a combination of an muscarinic agonist and an inverse agonist of the GABAA xcex15 receptor subtype, and the use of the combination in treating neurodegenerative conditions such as Alzheimer""s Disease.
Alzheimer""s Disease is a poorly understood neurodegenerative condition mainly affecting the elderly but also younger people who are generally genetically predispositioned to it.
One postulated method of treatment comprises the administration of muscarinic agonists which act on the cholinergic system. However this method suffers from the disadvantages that these compounds induce a range of side-effects including diarrhoea, salivation and nausea.
The present invention provides a new and surprisingly effective synergistic combination of an muscarinic agonist and an inverse agonist of the GABAA xcex15 receptor subtype for separate, sequential or simultaneous administration.
The present invention provides a greater than expected improvement in the condition of subjects suffering from a neurodegenerative with an associated cognitive deficit, such as Alzheimer""s Disease or Parkinson""s disease, or from a cognitive deficit which may arise from a normal process such as aging or from an abnormal process such as injury, than would be expected from administration of the active ingredients alone. Further, the combination allows for a lower overall dose of each of the active ingredients to be administered thus reducing side effects and decreasing any reduction in the effectiveness of each of the active ingredients over time.
Muscarinic agonists which may be used include any which are known to the skilled person. Examples are methacholine and its chloride, carbachol, bethanechol, arecholine, pilocarpine, muscarine, McN-A-343, oxotremorine, milameline, xanomeline, cis-methyldioxalane, pirenzepine, gallamine, SB 202026, AF102B, AFDX 116 and RS-86.
Any inverse agonist of the GABAA xcex15 receptor subtype may be used which fulfills the criteria of WO-A-9625948. The inverse agonist may be either binding selective for the xcex15 subtype or functionally selective, or both. Thus the inverse agonist is preferably an antagonist, or has insignificant agonist or inverse agonist properties at the other GABAA xcex1 receptor subtypes when measured in oocytes as described in WO-A-9625948.
Thus the inverse agonist preferably has a functional efficacy at the xcex15 receptor subunit of less than xe2x88x9220% and functional efficacies at the xcex11, xcex12, and xcex13 receptor subunits of between xe2x88x9220 and +20%. By functional efficacy is meant the percentage modulation of the EC20 response produced by GABA, upon coadministration of the inverse agonist, in oocytes expressing GABAA receptor channels containing the xcex1 receptor subunit under test. Details of this measurement are given in WO-A-9625948.
The inverse agonist preferably binds selectively to GABAA receptors containing the xcex15 subunit 10, 25 and particularly 50 times compared to GABAA receptors subunits containing the xcex11, xcex12 or xcex13 subunits. Preferably this binding selectivity is shown over all these subunits.
A preferred class of inverse agonists, which are disclosed in WO-A-9850385, are of formula I: 
wherein:
R1 is hydrogen, halogen or CN or a group C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C2-4alkenyloxy or C2-4alkynyloxy, each of which groups is unsubstituted or substituted with one or two halogen atoms or with a pyridyl or phenyl ring each of which rings may be unsubstituted or independently substituted by one or two halogen atoms or nitro, cyano, amino, methyl or CF3 groups;
R2 is hydrogen, halogen or CN or a group C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C2-4alkenyloxy or C2-4alkynyloxy each of which groups is unsubstituted or substituted with one or two halogen atoms;
L is O, S or NRn, where Rn is H, C1-6alkyl or C3-6cycloalkyl;
X is a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur, or a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, the 5- or 6-membered heteroaromatic ring being optionally fused to a benzene ring and the heteroaromatic ring being optionally substituted by Rx and/or Ry and/or Rz, where Rx is halogen, R3, OR3, OCOR3, NR4R5, NR4COR5, tri(C1-6alkyl)silylC1-6alkoxyC1-4alkyl, CN or R9, Ry is halogen, R3, OR3, OCOR3, NR4R5, NR4COR5 or CN and Rz is R3, OR3 or OCOR3, where R3 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, hydroxyC1-6alkyl and R3 is optionally mono, di- or tri-fluorinated, R4 and R5 are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or CF3 or R4 and R5, together with the nitrogen atom to which they are attached, form a 4-7 membered heteroaliphatic ring containing the nitrogen atom as the sole heteroatom, and R9 is benzyl or an aromatic ring containing either 6 atoms, 1, 2 or 3 of which are optionally nitrogen, or 5 atoms, 1, 2 or 3 of which are independently chosen from oxygen, nitrogen and sulphur, at most one of the atoms being oxygen or sulphur, and R9 is optionally substituted by one, two or three substituents independently chosen from halogen atoms and C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C2-4alkenyloxy and C2-4alkynyloxy groups each of which groups is unsubstituted or substituted by one, two or three halogen atoms, and when X is a pyridine derivative, the pyridine derivative is optionally in the form of the N-oxide and providing that when X is a tetrazole derivative it is protected by a C1-4alkyl group; or X is phenyl optionally substituted by one, two or three groups independently selected from halogen, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and C3-6cycloalkyl;
Y is optionally branched C1-4alkylidene optionally substituted by an oxo group or Y is a group (CH2)jO wherein the oxygen atom is nearest the group X and j is 2, 3 or 4;
Z is a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur and providing that when two of the heteroatoms are nitrogen an oxygen or sulphur atom is also present and that when one of the atoms is oxygen or sulphur then at least one nitrogen atom is present, or a 6-membered heteroaromatic ring containing 2 or 3 nitrogen atoms, Z being optionally substituted by Rv and/or Rw, where Rv is halogen, R6, NR7R8, NR7COR8, CN, furyl, thienyl, phenyl, benzyl, pyridyl or a 5-membered heteroaromatic ring containing at least one nitrogen atom and optionally 1, 2 or 3 other heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the other heteroatoms being oxygen or sulphur and Rw is R6 or CN;
R6 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, hydroxyC1-6alkyl, C1-6alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, CH2F or CF3; and
R7 and R8 are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or CF3 or R7 and R8, together with the nitrogen atom to which they are attached, form a 4-7 membered heteroaliphatic ring containing the nitrogen atom as the sole heteroatom;
or a pharmaceutically acceptable salt thereof.
As used herein, the expression xe2x80x9cC1-6alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as xe2x80x9cC1-4alkylxe2x80x9d, xe2x80x9cC2-4alkenylxe2x80x9d, xe2x80x9cC2-6alkenylxe2x80x9d, xe2x80x9chydroxyC1-6alkylxe2x80x9d, xe2x80x9cC2-4alkylxe2x80x9d and xe2x80x9cC2-6alkynylxe2x80x9d are to be construed in an analogous manner.
The expression xe2x80x9cC3-6cycloalkylxe2x80x9d as used herein includes cyclic propyl, butyl, pentyl and hexyl groups such as cyclopropyl and cyclohexyl.
Suitable 5- and 6-membered heteroaromatic rings include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl and thiadiazolyl groups. A suitable 5-membered heteroaromatic ring containing four nitrogen atoms is tetrazolyl. Suitable 6-membered heteroaromatic rings containing three nitrogen atoms include 1,2,4-triazine and 1,3,5-triazine.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
As used herein the term xe2x80x9cC1-6alkoxyxe2x80x9d includes methoxy and ethoxy groups, and straight-chained, branched and cyclic propoxy, butoxy, pentoxy and hexoxy groups, including cyclopropylmethoxy. Derived expressions such as xe2x80x9cC2-6alkenyloxyxe2x80x9d, xe2x80x9cC2-6alkynyloxyxe2x80x9d, xe2x80x9cC1-4alkoxyxe2x80x9d, xe2x80x9cC2-4alkenyloxyxe2x80x9d and xe2x80x9cC2-4alkyloxyxe2x80x9d should be construed in an analogous manner.
Four particular compounds which can be used are:
6-(1-methylimidazol-4-yl)methyloxy-3-(5-methylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine;
3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine;
3-(5-methylisoxazol-3-yl)-6-(2-pyridyl)-1,2,4-triazolo[3,4-a]phthalazine; and
3-(5-methylisoxazol-3-yl)-6-(1-methylimidazol-4-yl)- 1,2,4-triazol-3-ylmethyloxy-1,2,4-triazolo[3,4-a]phthalazine.
The second of the above compounds is particularly favoured.
The present invention also provides a pharmaceutical composition comprising an muscarinic agonist, an inverse agonist of the GABAA xcex15 receptor subtype and a pharmaceutically acceptable carrier.
There is also provided a kit of parts comprising a first pharmaceutical composition comprising an muscarinic agonist and a first pharmaceutically acceptable carrier and a second pharmaceutical composition comprising an inverse agonist of the GABAA xcex15 receptor subtype and a second pharmaceutically acceptable carrier for simultaneous, sequential or separate administration.
There is further provided a combination of an muscarinic agonist and an inverse agonist of the GABAA xcex15 receptor subtype for use in a method of treatment of the human body, particularly for the treatment of a neurodegenerative disorder with associated cognitive deficit such as Alzheimer""s Disease or Parkinson""s disease, or of a cognitive deficit arising from a normal process such as aging or of an abnormal process such as injury. The combination is particularly beneficial in the treatment of Alzheimer""s Disease.
There is also provided the use of a combination of an muscarinic agonist and an inverse agonist of the GABAA xcex15 receptor subtype in the manufacture of a medicament for the treatment of a neurodegenerative disorder such as Alzheimer""s Disease or Parkinson""s disease, or of a cognitive deficit arising from a normal process such as aging or of an abnormal process such as injury. The treatment of Alzheimer""s Disease is particularly preferred.
There is also disclosed a method of treatment of a subject suffering from a neurodegenerative disorder, such as Alzheimer""s Disease or Parkinson""s disease, or a cognitive deficit arising from a normal process such as aging or an abnormal process such as injury, which comprises administering to that subject a therapeutically effective amount of a combination of an muscarinic agonist and an inverse agonist of the GABAA xcex15 receptor subtype. The treatment of Alzheimer""s Disease is particularly preferred.